Heterocyclic substituted imidazoloquinoxalinones, their preparation and their use

ABSTRACT

Imidazoloquinoxalinones of the formula ##STR1## where R 1  -R 5 , A and B have the meanings stated in the description, and their preparation are described. The novel substances are suitable for controlling diseases.

The present invention relates to novel imidazoloquinoxalinones withheterocyclic substituents, to processes for their preparation and totheir use for controlling diseases.

What are called excitatory amino acids, especially glutamic acid, arewidespread in the central nervous system. This excitatory amino acidacts as transmitter substance for glutamate receptors, of which varioussubtypes are known. One subtype is, for example, named after thespecific agonist N-methyl-D-aspartate the NMDA receptor. This NMDAreceptor has various binding sites for agonists and antagonists. Theamino acid glycine likewise binds to the NMDA receptor and modulates theeffect of the natural agonist glutamic acid. Antagonists at this glycinebinding site may accordingly show antagonistic effects on the NMDAreceptor and inhibit overexcitation of this receptor.

Two other subtypes of glutamate receptors are the AMPA receptor and thekainate receptor, which are each named after the specific agonists2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainicacid. Antagonists of these receptors might, similar to theabovementioned NMDA receptor, likewise inhibit overexcitation.

Elevated glutamate levels occur in a number of neurodegenerativediseases or psychological disturbances and may lead to overexcitationstates or toxic effects in the CNS.

Antagonists of glutamate receptor subtypes may thus be used to treatthese diseases. Glutamate antagonists, which include, in particular,NMDA antagonists and their modulators (such as glycine antagonists) andthe AMPA antagonists, are therefore suitable for therapeutic use forneurodegenerative diseases (Huntington's chorea and Parkinson'sdisease), neurotoxic disturbances following hypoxia, anoxia or ischemia,as occur after stroke, or else as antiepileptics, antidepressants andanxiolytics (cf. Arzneim. Forschung 40 (1990) 511-514; TIPS, 11 (1990)334-338 and Drugs of the Future 14 (1989) 1059-1071).

A number of imidazoloquinoxalinones of the formula II have beendisclosed: ##STR2##

Thus, DE-A 3 004 750 and DE-A 3 004 751 describe substances which haveantiallergic effects. Imidazoloquinoxalinones as phosphodiesteraseinhibitors are furthermore claimed as cardiovascular agents in U.S. Pat.No. 5,166,344 (=EP 400583).

In the CNS sector, U.S. Pat. No. 5,182,386 claims imidazoloquinoxalineswhich are antagonists or inverse agonists of the GABA receptor and canbe used to control anxiety states, sleep disturbances, convulsive statesand to improve memory.

Glutamate antagonists described in numerous publications (eg. EP 374 534and EP 260 467) are predominantly derivatives of quinoxaline-2,3-dione.

For example, WO 92/07847 relates to compounds with heterocyclicsubstituents in the benzenoid ring. U.S. Pat. No. 5,153,196 and U.S.Pat. No. 5,196,421, and WO 93/20077, relate to fused heterocycles,including the imidazoloquinoxalinone system. The latter also disclosessubstitution by heterocycles with 2-4 nitrogen atoms in the benzenoidpart of the ring system.

However, the compounds published as glutamate antagonists have onlyalkyl, trifluoromethyl or phenyl substituents in the fused-on imidazolering. It has now been found that substitution of theimidazoloquinoxalinone with heterocycles in the benzenoid part andcarboxylic acids or esters thereof in the fused-on imidazole ring leadsto novel, superior glutamate antagonists. They are thereforeparticularly suitable for the therapy of neurological disturbances whichcan be influenced thereby.

The invention relates to novel imidazoloquinoxalinones of the formula I##STR3## where R¹ is hydrogen, branched or straight-line C₁₋₅ -alkyl ora phenyl, pyridyl or thienyl group which is unsubstituted or substitutedby one or two chlorine atoms, one trifluoromethyl, one nitro ormethylenedioxy group,

R² is hydrogen, C₁₋₅ -alkyl or C₃₋₈ -dialkylaminoalkyl,

R³ is a chlorine or bromine atom, a trifluoromethyl, cyano or nitrogroup,

A is a five-membered heterocycle which is unsubstituted or substitutedby R⁴ and R⁵ and has 1-4 nitrogen atoms or has 1-2 nitrogen atoms andone oxygen or sulfur atom, where each of the radicals R⁴ and R⁵, whichcan be identical or different, is hydrogen, C₁₋₅ -alkyl, C₁₋₅-hydroxyethyl, phenyl, phenyl substituted by a chlorine atom, atrifluoromethyl or nitro group, or --COOH, --COO--C₁₋₅ -alkyl, --CH₂--NR⁶ R⁷ (R⁶ =H, C₁₋₅ -alkyl, R⁷ =H, C₁₋₅ -alkyl), --CH₂ --NH--CO--R⁸(R⁸ =C₁ -C₅ -alkyl, phenyl, a phenyl group which is unsubstituted orsubstituted by a chlorine atom or a nitro or trifluoromethyl group, or ahetaryl group) or --CH₂ NHCONHR⁸ and

B is a bond or a C₁₋₅ -alkylene chain and the tautomeric and isomericforms thereof and the physiologically tolerated salts thereof.

Preferred compounds of the formula I are those where R¹ is methyl, ethylor phenyl. R² is preferably methyl or ethyl or else a hydrogen atom.When R² is hydrogen, the compounds are acids able to form salts withalkali metal and alkaline earth metal hydroxides or organic nitrogenbases. The acids can, if required, be converted into a water-solubleform by formation of a salt with, for example, sodium hydroxide ortris(hydroxymethyl)methylamine.

Preferred substituents for R³ are electron-attracting groups such asnitro or trifluoromethyl in position 7.

Preferred 5-membered ring heterocycles for A are pyrrole and itsderivatives. Preferred pyrrole derivatives are 3-formylpyrrole, acylderivatives of 3-aminomethylpyrrole such as the benzoyl orpyridinecarbonyl derivatives, or those having an arylurea group, andsubstitution of the benzoyl group by a nitro or CF₃ group may beparticularly emphasized. Preferred among the 5-membered ring systemswith 2 nitrogen atoms are the imidazole system and its derivatives, alsobenzimidazole and pyrazole, and examples of 5-membered ring heterocycleswith 3 and 4 nitrogen atoms are 1,2,3-triazole, 1,2,4-triazole and theirderivatives, and the tetrazole system.

B is preferably a bond.

The present imidazoloquinoxalinones with heterocyclic substituentssurprisingly show advantages compared with previously disclosedimidazoloquinoxalinones, in particular higher activity.

The compounds according to the invention can be prepared in a variety ofways.

8-Aminoimidazoloquinoxalinones of the formula III ##STR4## where R¹, R³and B have the abovementioned meanings, and R² is alkyl, are reactedwith 1,4-dicarbonyl compounds or succinaldehyde derivatives, or cyclicor acyclic acetals derived therefrom, eg. formula IV ##STR5## to givethe pyrroles.

Compounds of the formula IV are available or can be prepared bygenerally known operations.

The conversion into pyrrolyl compounds is carried out by conventionalprocesses which are detailed, for example, in C. Ferri, "Reaktionen derorganischen Synthese", Thieme Verlag 1978, pp. 708 et seq., preferablyin glacial acetic acid at 60-120° C. Pyrrolyl compounds V according tothe invention can be prepared by using appropriately substituteddiketones or acetals of the formula IV. ##STR6##

The substitution R⁴ or R⁵ in the pyrrolyl compounds prepared in this waycan be altered in a suitable manner. Thus, for example, an aldehydegroup can be converted by reduction into a hydroxyalkyl or by reductiveamination into an aminoalkyl group.

The reductive amination is generally carried out at from 5 to 80° C.,preferably 10 to 30° C., in the presence of reducing agents such assodium cyanoborohydride or hydrogen in the presence of hydrogenationcatalysts such as Pd/carbon, Pt/carbon or Raney nickel, expediently inpolar organic solvents such as alcohols or dimethylformamide.

An aldehyde can be oxidized by conventional processes which aredescribed, for example, in R. C. Larock "Comprehensive OrganicTransformations", 1989, VCH Publisher, pp. 838 et seq., to thecarboxylic acid according to the invention, and the oxidation ispreferably carried out with potassium permanganate in solvents such asacetone at 25° C.

The starting compounds of the formula VI where R³ has theabove-mentioned meaning but is not nitro can be prepared by a processsimilar to that described in EP 400 583 with subsequent nitration andreduction of the nitro group as shown in Scheme 1:

Scheme 1 ##STR7##

It is known that ortho-halo-substituted nitrobenzenes (VI) can bereacted with imidazoles VII which are unsubstituted on the N₁ nitrogenatom in suitable solvents, such as dimethyl sulfoxide, dimethylformamideor acetonitrile, at from 0 to 140° C. with addition of base, eg.potassium carbonate.

It is furthermore known that replacement of the halogen atom by4-substituted and 4,5-disubstituted imidazoles takes place bynucleophilic attack on the least sterically hindered nitrogen atom ofthe imidazole to result in single products (VIII).

Reduction of the nitro compounds to aniline derivatives IX can takeplace in a conventional way, for example by catalytic hydrogenation withpalladium or nickel catalysts or else with tin(II) chloride.

o-Halonitrobenzenes of the formula VI can be bought or can be preparedby known methods.

Ring closure to the imidazoloquinoxalinone X takes place with a doublyactivated carbonic acid derivative such as phosgene, diphenyl carbonateor, preferably, N,N'-carbonyldiimidazole in an inert aprotic solvent at150-200° C. Suitable solvents are decalin, tetralin, 1,2-dichlorobenzeneor 1,3-dimethylethylene- or -propyleneurea. One process for preparingthe nitro compounds XI comprises nitrating compounds X (R³ as above butnot nitro) with nitric acid, sulfuric acid/nitric acid or sulfuricacid/potassium nitrate at from -10° to 20°.

Reduction of the nitro group as described above results in startingcompounds III suitable for preparing the pyrrolyl compounds V.

Another process for preparing the substances according to the inventioncomprises first reacting, as described previously, a nitrobenzenederivative XII which has two exchangeable halogen atoms with animidazole derivative VII to give compounds VIII b, and carrying out asecond reaction with a nitrogen heterocycle XIII to give compounds XIVand, after reduction of the nitro group, cyclizing the resultingcompounds as described above: ##STR8##

R¹ -R⁵, A and B have the abovementioned meanings.

Particularly suitable heterocycles of the formula XIII are compoundswhich have an NH group which can be substituted and are derived from thenitrogen heterocycles imidazole, pyrazole, 1,2,3-triazole,1,2,4-triazole and tetrazole. However, suitable heterocycles may alsocontain another hetero atom such as an oxygen or sulfur atom.

The process can, where appropriate, also be carried out by reacting anappropriate nitrobenzene XV which has two exchangeable halogen atoms anda protected amino group located in the correct position for the finalcyclization first with the required heterocycle XIII and then with therequired imidazole derivative VII to give XVI and, after removal of theamino protective group to give XVII, carrying out the ring closure asdescribed previously:

Scheme 3 ##STR9##

Another process for preparing the compounds I according to the inventionwhere R³ is nitro comprises initial nitration of a compound XVIII##STR10## in position B (XIX), and then reduction to XX ##STR11##protection of the amino group, renewed nitration in position 7 andliberation of the o-amino nitro compounds XX, which are suitable forfurther reaction with, for example, furan derivatives IV, by removal ofthe protective group. ##STR12##

Compounds of the formula I where R¹, R², R³, R⁴, R⁵, A and B have theabovementioned meanings can be converted by hydrolysis into acids of theformula I where R¹, R³, R⁴, R⁵, A and B have the stated meanings, and R²is hydrogen.

The hydrolysis is preferably carried out under alkaline conditions, forexample in the presence of an alkali metal hydroxide or of sodiumbicarbonate, in a solvent such as water, a lower alcohol,tetrahydrofuran or mixtures thereof. The organic acids obtained in thisway are converted where appropriate into a physiologically toleratedamine salt or metal salt. This means, in particular, salts of the alkalimetals such as sodium and potassium, of the alkaline earth metals suchas calcium, of other metals such as aluminum, and salts of organic basessuch as morpholine, piperidine, mono-, di- and triethanolamine ortris-(hydroxymethyl)aminomethane.

The compounds according to the invention are antagonists of theexcitatory amino acid glutamate, in particular antagonists of theglycine binding site of the NMDA receptor, of the AMPA receptor and ofthe kainate receptor.

They are suitable as pharmaceutical agents in human medicine and can beused to produce drugs for treating neurodegenerative disorders andneurotoxic disturbances of the central nervous system and for producingspasmolytics, antiepileptics, anxiolytics and antidepressants.

The pharmacological activity of the compounds I was investigated onisolated membrane material from rat cerebra. For this purpose, themembranes were incubated in the presence of the compounds according tothe invention with the radiolabeled substances ³H-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (³ H-AMPA), [³H]-glycine and [³ H]-kainate, which bind specifically to AMPA, NMDA andkainate receptors respectively. After this incubation, the radioactivitymeasured by scintillation counting was used to determine the extent ofthe binding of the said radioactive receptor ligands to the membranereceptors. The affinity of the compounds according to the invention forthe relevant receptors was calculated from the concentration-dependentdisplacement of this binding by the compounds according to theinvention. The dissociation constant K_(I) (as measure of the affinity)was determined by iterative non-linear regression analysis using theStatistical Analysis System (SAS), similar to the ligand program of P.J. Munson and D. Rodbard (Analytical Biochem. 107 (1980) 220, Ligand:Versatile Computerized Approach for Characterization of Ligand BindingSystems).

The following in vitro investigations were carried out:

1. Binding of ³ H-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(³ H-AMPA)

To prepare the membrane material, freshly removed rat cerebra werehomogenized with 15 times the volume of a buffer solution A composed of30 mM α,α,α-tris(hydroxymethyl)methylamine hydrochloride (TRIS-HCl) and0.5 mM ethylenediaminetetraacetic acid (EDTA), pH 7.4, using anUltra-Turax®. The suspension was centrifuged at 48000 g for 20 min.After removal of the supernatant liquid, the protein-containing membranematerial contained in the sediment was washed three times by suspensionin buffer solution A and subsequent centrifugation at 48 000 g for 20minutes each time. The membrane material was then suspended in 15 timesthe volume of buffer solution A and incubated at 37° C. for 30 min. Theprotein material was subsequently washed twice by centrifugation andsuspension and stored at -70° C. until used.

For the binding assay, the protein material was thawed at 37° C. andwashed twice by centrifugation at 48 000 g (20 min) and subsequentsuspension in buffer solution B composed of 50 mM TRIS-HCl, 0.1Mpotassium thiocyanate and 2.5 mM calcium chloride, pH 7.1. Subsequently,0.25 mg of membrane material, 0.1 μCi of ³ H-AMPA (60 Ci/mmol) andcompound I were dissolved in 1 ml of buffer solution B and incubated onice for 60 min. The incubated solution was filtered through a CF/Bfilter (from Whatman) which had previously been treated with a 0.5%strength aqueous solution of polyethyleneimine for at least 2 hours. Themembrane residue was then washed with 5 ml of cold buffer solution B toseparate bound and free ³ H-AMPA from one another. After measurement ofthe radioactivity of bound ³ H-AMPA in the membrane material byscintillation counting, the K_(I) was determined by regression analysisof the displacement plots.

2. Binding of [³ H]-glycine

To prepare the membranes for the ³ H-glycine binding assay, freshlyremoved rat hippocampi were homogenized in 10 times the volume ofpreparation buffer (50 mM tris-HCl, 10 mM EDTA) using a Potterhomogenizer. The homogenate was centrifuged at 48000×g for 20 min. Thesupernatant was discarded, and the membranes contained in the pelletwere washed 2× by resuspension and centrifugation at 48000×g (20 mineach time). The resuspended membranes were frozen in liquid nitrogen andthawed again at 37° C. After another washing step, the membranesuspension was incubated in a shaking water bath at 37° C. for 15 min.After a further 4 washing steps (in each case centrifugation at 48000×gfor 20 minutes and resuspension in preparation buffer), the membraneswere stored at -70° C. until used further.

The frozen membranes were thawed at 37° C. and washed 2× bycentrifugation at 48000×g (20 min) and subsequent resuspension inbinding buffer (50 mM tris-HCl pH 7.4; 10 mM MgCl₂). An incubationmixture contained 0.25 mg of protein (membranes), 25 nM ³ H-glycine (16Ci/mMol) and the substances to be tested in a total of 0.5 ml of bindingbuffer. The non-specific binding was determined adding 1 mM glycine.After incubation at 4° C. for 60 min, separation of bound and freeligand from one another took place by filtration through GF/B filtersand subsequent washing with about 5 ml of ice-cold binding buffer. Theradioactivity remaining on the filters was determined by liquidscintillation counting. The dissociation constants were calculated fromthe displacement plots using an iterative non-linear fitting program orin accordance with the equation of Cheng and Prusoff.

3. Binding of [³ H]-kainate

To prepare the membranes for the [³ H]-kainate binding assay, freshlyremoved rat cerebra were homogenized in 15 times the volume ofpreparation buffer (30 mM Tris-HCl pH 7.4, 0.5 mM EDTA) using anUltra-Turrax®. The homogenate was centrifuged at 48000×g for 20 min. Thesupernatant was discarded, and the membranes contained in the pelletwere washed a total of 3× by resuspension in preparation buffer andcentrifugation at 48000×g (20 min each time). After the third washingstep, the membranes were incubated at 37° C. The membranes were thenwashed 2× by centrifugation and resuspension and stored at -70° C. untilused further.

The frozen membranes were thawed at 37° C., suspended in binding buffer(50 mM tris-HCl pH 7.4) and centrifuged at 48000×g for 20 min. Themembranes present in the pellet were resuspended in binding buffer. Anincubation mixture contained 0.25 mg of protein (membranes), 0.058 μCiof [³ H]-kainate (58 Ci/mmol) and the substances to be tested in a totalof 1 ml of binding buffer. The non-specific binding was determined inthe presence of 0.1 mM glutamate. After incubation on ice for 60minutes, separation of bound and free ligand took place by filtrationthrough CF/B filters and subsequent washing with 5 ml of ice-coldbinding buffer. The CF/B filters had previously been treated with 0.5%polyethyleneimine for at least 2 h. The analysis of the displacementplots and calculation of the dissociation constants took place using anon-linear fitting program or in accordance with the equation of Chengand Prusoff.

The novel compounds perform very well in these assays.

The pharmaceutical compositions according to the invention contain atherapeutically effective amount of the compounds I in addition toconventional pharmaceutical ancillary substances. The agents can bepresent in conventional concentrations for local external use, eg. industing powders and ointments. As a rule, the agents are present in anamount of from 0.0001 to 1% by weight, preferably 0.001 to 0.1% byweight.

For internal use, the preparations are administered in single doses.From 0.1 to 100 mg are administered per kg of body weight in a singledose. The compositions can be administered in one or more doses each daydepending on the nature and severity of the disorders.

The pharmaceutical compositions according to the invention contain,besides the agent, the conventional excipients and diluents appropriatefor the required mode of administration. Pharmaceutical ancillarysubstances which can be used for local external use are, for example,ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenatedcastor oil, polyacrylic acid, polyethylene glycol, polyethylene glycolstearate, ethoxylated fatty alcohols, liquid paraffin, petrolatum andwool fat. Suitable examples for internal use are lactose, propyleneglycol, ethanol, starch, talc and polyvinylpyrrolidone.

It is furthermore possible for antioxidants such as tocopherol andbutylated hydroxyanisole, and butylated hydroxytoluene, flavoringadditives, stabilizers, emulsifiers and lubricants to be present.

The substances present in the composition in addition to the agent, andthe substances used for producing the pharmaceutical composition aretoxicologically acceptable and compatible with the agent in each case.The pharmaceutical compositions are produced in a conventional way, eg.by mixing the agent with the conventional excipients and diluents.

The pharmaceutical compositions can be administered in various ways,such as orally, parenterally, subcutaneously, intraperitoneally andtopically. Thus, possible presentations are tablets, emulsions, infusionand injection solutions, pastes, ointments, gels, creams, lotions,dusting powders and sprays.

EXAMPLES Example 1

Ethyl4,5-dihydro-1-methyl-8-(1-pyrrolyl)-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

a. 1-(2-Nitro-4-trifluoromethylphenyl)-4-carbethoxy-5-methylimidazole

A mixture of 10.45 g (0.05 mol) of2-fluoro-4-trifluoromethylnitrobenzene, 7.7 g (0.05 mol) of4(5)-carbethoxy-5(4)-methylimidazole and 13.8 g of potassium carbonatein 100 ml of acetonitrile was refluxed for 4 h.

1000 ml of water were added to the cooled reaction mixture, the mixturewas extracted with 250 ml of methylene chloride, and the methylenechloride phase was dried with magnesium sulfate. The dried solution wasevaporated, and the residue was induced to crystallize by triturationwith ether.

Yield: 11.4 g (66% of theory); Melting point: 142-144° C.

b. 1-(2-Amino-4-trifluoromethylphenyl)-4-carbethoxy-5-methylimidazole

11.6 g (0.034 mol) of compound a. described above were hydrogenated with2 g of palladium/carbon catalyst (10% Pd) in 100 ml of ethanol underatmospheric pressure at room temperature. After hydrogen uptake ceased,the catalyst was removed from the solution which was then evaporatedunder reduced pressure, and the residue was induced to crystallize witha little ether.

Yield: 9.8 g (93% of theory); Melting point: 189-190° C.

c. Ethyl4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

7.3 g (0.0233 mol) of compound b. described above and 4.2 g (0.0259 mol)of N,N'-carbonyldiimidazole in 100 ml of 1,2-dichlorobenzene were boiledwith stirring for 2.5 h. After cooling, the solid was filtered off withsuction and washed with acetone/ether.

Yield: 5.1 g (64.5% of theory); Melting point: 270-271° C.

d. Ethyl4,5-dihydro-1-methyl-8-nitro-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

5.0 g (0.015 mol) of compound c. described above were nitrated with amixture of 50 ml of concentrated sulfuric acid and 50 ml of nitric acid(d=1.50) at room temperature for 72 h and subsequently at 60° C. for 1h. The mixture was cooled and then poured onto ice, and the product wasfiltered off with suction and washed with water.

Yield: 3.9 g (70% of theory); Melting point: 284-286° C.

e. Ethyl8-amino-4,5-dihydro-1-methyl-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

12 g (0.031 mol) of compound d. described above were dissolved in 200 mlof boiling glacial acetic acid and subsequently 15 g of iron powder wereintroduced in portions over the course of 15 min. After 30 min, theprecipitate was filtered off with suction and washed with acetic acid,water and methanol.

Yield: 10 g (91% of theory); Melting point: 300° C.

f. 1.5 g (0.0042 mol) of compound e. described above were taken up in 30ml of glacial acetic acid, 1.12 g (0.085 mol) of2,5-dimethoxytetrahydrofuran were added, and the mixture was rapidlyheated to boiling in a preheated oil bath until a solution was obtained.The mixture was rapidly cooled after 5 min, and the precipitate wasfiltered off with suction and washed with acetic acid and ether.

Yield: 0.75 g (44% of theory); Melting point: 290-295° C.; C₁₉ H₁₅ F₃ N₄O₃

Further compounds were prepared as in process 1f using the following2,5-dimethoxytetrahydrofuran derivatives substituted in position 3.

2,5-Dimethoxytetrahydrofuran derivatives: ##STR13##

The compounds obtained therefrom are shown in Table I:

    __________________________________________________________________________    Ex. No.                                                                           Structural formula               Molecular formula                                                                      Melting point                   __________________________________________________________________________      2                                                                                                                           CSTR14##                                                                    .sub.20 H.sub.15 F.sub.3                                                      N.sub.4 O.sub.4 292-296.degr                                                  ee. C.                             - 3                                                                                                                        C.sub.27 H.sub.23 F.sub.3                                                   N.sub.6 O.sub.4 >300°                                                   C.                                - 4                                                                                                                        C.sub.27 H.sub.23 F.sub.3                                                   N.sub.7 O.sub.6 225-230.degr                                                  ee. C.                             - 5                                                                                                                        C.sub.22 H.sub.20 F.sub.3                                                   N.sub.5 O.sub.4 198-200.degr                                                  ee. C.                             - 6                                                                                                                        C.sub.22 H.sub.19 F.sub.3                                                   N.sub.4 O.sub.4 235-239.degr                                                  ee. C.                             - 7                                                                                                                        C.sub.26 H.sub.21 F.sub.3                                                   N.sub.6 O.sub.4 268-270.degr                                                  ee. C.                             - 8                                                                                                                        C.sub.27 H.sub.22 F.sub.3                                                   N.sub.5 O.sub.4 230-231.degr                                                  ee. C.                          __________________________________________________________________________

Example 9

Ethyl4,5-dihydro-8-(2,5-dimethyl-1-pyrrolyl)-1-methyl-7-triluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

1.0 g (0.0028 mol) of the compound of Example 1e was boiled togetherwith 2 g of acetonylacetone in 25 ml of acetic acid, a solution beingobtained after 5 min. After heating for a further 10 min, the mixturewas cooled, and the precipitate was filtered off with suction, washedwith ether and dried under reduced pressure.

Yield: 0.9 g (75% of theory); Melting point >300° C.; C₂₁ H₁₉ F₃ N₄ O₃

Example 10

4,5-Dihydro-1-methyl-8-(1-pyrrolyl)-7-trifluoromethyl-4-oxoimidazolo[1,2-a]-quinoxaline-2-carboxylicacid

0.5 g of the ester prepared in Example 1f was dissolved in a solution of1 g of LiOH in 50 ml of water by brief heating at 80° C. After somehours, the mixture was acidified to pH 5 with acetic acid, and theprecipitate was filtered off with suction and dried under reducedpressure.

Yield: 0.4 g (86% of theory); Melting point >300° C.; C₂₁ H₁₉ F₃ N₄ O₃

The following compounds were obtained in a similar manner from theesters of Examples 2-9:

    __________________________________________________________________________    Ex. No.                                                                           Structural formula               Molecular formula                                                                      Melting point                   __________________________________________________________________________      11                                                                                                                          CSTR21##                                                                    .sub.18 H.sub.11 F.sub.3                                                      N.sub.4 O.sub.4 >300°                                                   C.                                - 12                                                                                                                       C.sub.25 H.sub.19 F.sub.3                                                   N.sub.6 O.sub.4 >300°                                                   C.                                - 13                                                                                                                       C.sub.26 H.sub.21 F.sub.3                                                   N.sub.6 O.sub.4 >300°                                                   C.                                - 14                                                                                                                       C.sub.26 H.sub.20 F.sub.3                                                   N.sub.7 O.sub.6 290-295.degr                                                  ee. C.                             - 15                                                                                                                       C.sub.25 H.sub.18 F.sub.3                                                   N.sub.7 O.sub.6 >300°                                                   C.                                - 16                                                                                                                       C.sub.25 H.sub.19 F.sub.3                                                   N.sub.6 O.sub.4 >300°                                                   C.                                - 17                                                                                                                       C.sub.19 H.sub.15 F.sub.3                                                   N.sub.4 O.sub.3 >300°                                                   C.                                - 18                                                                                                                       C.sub.20 H.sub.15 F.sub.3                                                   N.sub.4 O.sub.4 >300°                                                   C.                                - 19                                                                                                                       C.sub.25 H.sub.18 F.sub.3                                                   N.sub.5 O.sub.4 298-300.degr                                                  ee. C.                          __________________________________________________________________________

20.4,5-Dihydro-8-(1-imidazolyl)-1-methyl-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylicacid

a.1-(5-Chloro-2-nitro-4-trifluoromethylphenyl)-4-carbethoxy-5-methylimidazoleprepared as in Example 1a from 2,4-dichloro-5-nitrobenzotrifluoride and4(5)-carbethoxy-5(4)-methylimidazole

Melting point 118-119° C.; C₁₄ H₁₁ CIF₃ N₃ O₄

b.4-(4-Carbethoxy-5-methyl-1-imidazolyl)-2-(1-imidazolyl)-5-nitrobenzotrifluoride5 g (0.013 mol) of the product prepared in Example 1a and 1.8 g (0.026mol) of imidazole in 100 ml of acetonitrile were refluxed for 120 h. Thesolvent was then removed by distillation, the residue was treated withethyl acetate and water, and the solvent phase was separated off, washedonce more with water, dried and evaporated. The product crystallizedafter trituration of the residue with a 99:1 mixture of diisopropylether in THF.

Melting point 160-162° C.; C₁₇ H₁₄ F₃ N₅ O₄

c.2-(4-Carbethoxy-5-methyl-1-imidazolyl)-4-(1-imidazolyl)-5-trifluoromethylaniline3.5 g of the product from Example 1b in 50 ml of acetic acid were heatedto boiling and then 5.6 g of iron powder were added in portions. After20 min, the mixture was filtered with suction, the solution wasevaporated under reduced pressure, water was added and the mixture wasextracted twice with ethyl acetate. The extract was then washed withsodium carbonate solution until free of acid, the solution was dried andevaporated, and the residue was digested with ether.

Yield: 1.8 g (55% of theory) Melting point 265-266° C.

d. Preparation of the final product 0.7 g (0.002 mol) of the compoundobtained in 20c and 0.5 g of 1,1'-carbonyldiimidazole in 50 ml of1,2-dichlorobenzene were refluxed for 2 h. The precipitate obtainedafter cooling was filtered off with suction and washed with a hotmethanol/isopropanol mixture.

The following was obtained: Yield 0.2 g (25% of theory); Melting point265-270° C.; C₁₈ H₁₄ F₃ N₅ O₃

The following were obtained in a similar way using different startingcompounds:

21. Ethyl4,5-dihydro-1-methyl-8-(2-methyl-1-imidazolyl)-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

Melting point >300° C.; C₁₉ H₁₅ F₃ N₄ O₃

22. Ethyl4,5-dihydro-1-methyl-8-(1,2,4-triazol-1-yl)-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

Melting point 291-293° C.; C₁₇ H₁₃ F₃ N₆ O₃

The following compounds were obtained from the compounds of Examples19-21 by hydrolysis with lithium hydroxide as in Example 10:

23.4,5-Dihydro-8-(1-imidazolyl)-1-methyl-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylicacid

Melting point 291-293° C.; C₁₇ H₁₃ F₃ N₆ O₃

24.4,5-Dihydro-1-methyl-8-(2-methyl-1-imidazolyl)-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylicacid

Melting point >300° C.; C₁₇ H₁₂ F₃ N₅ O₃

25.4,5-Dihydro-1-methyl-8-(1,2,4-triazol-1-yl)-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylicacid

Melting point >300° C.; C₁₇ H₁₂ F₃ N₅ O₃

26.4,5-Dihydro-1-ethyl-8-(1-imidazolyl)-7-trifluoromethyl-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylicacid

Melting point >300° C.; C₁₇ H₁₂ F₃ N₅ O₃

27. Ethyl4,5-dihydro-8-(3-formyl-1-pyrrolyl)-1-methyl-7-nitro-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate.

a. Preparation of the starting material:

Ethyl4,5-dihydro-1-methyl-4-oxoimidazolo[1,2-a]-quinoxaline-2-carboxylate wasprepared by reacting 2-fluoronitrobenzene with4(5)-carbethoxy-5(4)methylimidazole, followed by hydrogenation andsubsequent ring closure with N,N'-carbonyldiimidazole.

b. Ethyl4,5-dihydro-1-methyl-8-nitro-4-oxoimidazolo-[1,2-a]quinoxaline-2-carboxylate

25 g (0.09 mol) of the substance described above under a) wereintroduced in portions into 300 ml of 100% strength nitric acid whilestirring at 0-5° C. After 15 min, the mixture was poured onto ice andfiltered with suction, and the residue was treated with acetone toobtain crystals of the product.

Yield: 26 g (82% of theory); Melting point >300° C.; C₁₄ H₁₂ N₄ O₅

c. Ethyl4,5-dihydro-8-acetamido-1-methyl-4-oxoimidazolo-[1,2-a]quinoxaline-2-carboxylate

The compound described above under b) was reduced with iron powder inboiling acetic acid

Yield: 66% of theory; Melting point >300° C.; C₁₆ H₁₆ N₄ O₄

d. Ethyl4,5-dihydro-8-acetamido-1-methyl-7-nitro-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

1 g of the compound described under d) was nitrated by introduction inportions into 25 ml of 100% strength nitric acid at 20° C. followed bystirring for 5 min.

Yield: 0.8 g (70% of theory); Melting point >300° C.; C₁₆ H₁₅ N₅ O₆

e. Ethyl4,5-dihydro-8-amino-1-methyl-7-nitro-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

The preceding compound d) was selectively hydrolyzed with hydrochloricacid by initially heating the compound to 70° C. and then slowly coolingto room temperature.

Yield: 1.4 g (35% of theory); Melting point >300° C.; C₁₄ H₁₃ N₅ O₅

f. Preparation of the final product

1.0 g (0.003 mol) of the compound obtained in e) was reacted with 1.0 gof 2,5-dimethoxy-3-formyltetrahydrofuran in boiling glacial acetic acidas in Example 1f.

Yield: 0.3 g (24% of theory); Melting point 220-225° C.; C₁₉ H₁₅ N₅ O₆

28. Ethyl4,5-dihydro-1-methyl-8-(2-methyl-1-imidazolyl)-7-nitro-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

a. 5-Acetamido-4-fluoro-2-(2-methyl-1-imidazolyl)nitrobenzene

3 g (0.0138 mol) of 5-acetamido-2,4-difluoro-1-nitrobenzene were reactedwith 1.1 g (0.0135 mol) of 2-methylimidazole and 5 g of potassiumcarbonate in 50 ml of acetonitrile by stirring at 50° C. for 72 h. Forthe working up, the reaction mixture was filtered with suction,evaporated under reduced pressure and purified by column chromatography(silica gel, methylene chloride ±5% methanol).

Yield: 1.0 g (26% of theory); Melting point 209-210° C. (fromisopropanol); C₁₂ H₁₁ FN₄ O₃

b.5-Amino-2-(2-methyl-1-imidazolyl)-4-(4-carbethoxy-5-methyl-1-imidazolyl)nitrobenzene

6.0 g (0.022 mol) of the compound described under a) were reacted with3.4 g (0.022 mol) of 4(5)-carbethoxy-5(4)-methylimidazole and 6 g ofpotassium carbonate in 100 ml of DMF by stirring at 120° C. for 2 h. Forworking up, the mixture was filtered with suction, the solution wasevaporated under reduced pressure, water was added and the mixture wasextracted with methylene chloride. The residue obtained after drying andevaporation was recrystallized from isopropanol (Yield 3.5 g=39%) andthen stirred with 100 ml of hydrochloric acid at 60° C. for 4 h. Forworking up, the hydrochloric acid was substantially removed bydistillation under reduced pressure, and the product was neutralizedwith dilute ammonia at 0° C. and extracted with methylene chloride. Theresidue was purified by column chromatography.

Yield: 1 g

c. 1.0 g of the compound described under b) was reacted with 0.6 g ofN,N'-carbonyldiimidazole in 50 ml of 1,2-dichlorobenzene by stirring at160-170° C. for 2 h. After cooling to 50° C., the solution was decantedoff the precipitate, and the residue was treated with hot acetone andfiltered off with suction. The filtrate was evaporated to result in 0.1g of the desired compound.

Melting point 265-270° C.; C₁₈ H₁₆ N₆ O₅

29. Ethyl4,5-dihydro-1-methyl-8-(1-imidazolyl)-7-nitro-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylate

a. 5-Amino-4-fluoro-2-(1-imidazolyl)nitrobenzene

12 g (0.068 mol) of 5-amino-2,4-difluoronitrobenzene were slowly addedat 0° C. to a solution of 4.7 g of imidazole (0.069 mol) and 2.1 g ofsodium hydride (80% in oil; 0.07 mol) and then stirred at thistemperature for several hours. The mixture was then diluted with waterand extracted several times with methylene chloride. The residue afterdrying and evaporation was recrystallized from isopropanol.

Yield: 7.1 g (45% of theory); Melting point 211-212° C.

b.5-Amino-2-(1-imidazolyl)-4-(4-carbethoxy-5-methyl-1-imidazolyl)nitrobenzen

4.2 g (0.027 mol) of 4(5)-carbethoxy-5(4)-methylimidazole werepretreated with 0.82 g of sodium hydride (80% in oil; 0.027 mol) in 30ml of DMF for 1 h and then 6.1 g (0.027 mol) of the compound describedabove under a. were added and the mixture was stirred overnight. It wasthen heated at 50° C. for 1 h before working up. For working up, waterwas added, and then 3 ml of acetic acid were added and the mixture wasextracted with methylene chloride, followed by drying and evaporation.The compound was obtained as crystals after treatment withether/isopropanol (95+5).

Yield: 4.2 g (42% of theory); Melting point 213-215° C.

c. Preparation of the final product

1.0 g of the compound described under b. was reacted as described underExample 28c, and the compound according to the example was obtained in ayield of 0.3 g (24% of theory).

Melting point 328-330° C. C₁₈ H₁₃ N₅ O6

The following were obtained by hydrolysis of the compounds of Example 28and 29 with lithium hydroxide as in Example 10:

30.4,5-Dihydro-1-methyl-8-(1-imidazolyl)-7-nitro-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylicacid

Melting point >300° C.; C₁₅ H₁₀ N₆ O₅

31.4,5-Dihydro-1-methyl-8(2-methyl-1-imidazolyl)-7-nitro-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylicacid

Melting point >300° C.; C₁₆ H₁₂ N₆ O₅

32.4,5-Dihydro-8-(3-formyl-1-pyrrolyl)-1-methyl-7-nitro-4-oxoimidazolo[1,2-a]quinoxaline-2-carboxylicacid

The above compound was obtained by hydrolysis of the compound of Example27 with lithium hydroxide as in Example 10.

Melting point >300° C.; C₁₇ H₁₁ N₅ O₆

We claim:
 1. An imidazoloquinoxalinone of the formula I ##STR30## whereR¹ is hydrogen, branched or straight-line C₁₋₅ -alkyl or a phenyl,pyridyl or thienyl group which is unsubstituted or substituted by one ortwo chlorine atoms, one trifluoromethyl, one nitro or methylenedioxygroup,R² is hydrogen, C₁₋₅ -alkyl or C₃₋₈ -dialkylaminoalkyl, R³ is achlorine or bromine atom, a trifluoromethyl, cyano or nitro group, A ispyrrolyl, or 1,2,4-triazolyl, R⁴ and R⁵, which can be identical ordifferent, are hydrogen, C₁₋₅ -alkyl, C₁₋₅ -hydroxyethyl, phenyl, phenylsubstituted by a chlorine atom, a trifluoromethyl or nitro group, or--COOH, --COO--C₁₋₅ -alkyl, --CH₂ --NR⁶ R⁷, --CH₂ --NH--CO--R⁸ or --CH₂--NHCONHR⁸,where R⁶ is hydrogen or C₁₋₅ -alkyl, R⁷ is hydrogen or C₁₋₅-alkyl, and R⁸ is C₁₋₅ -alkyl, a phenyl group which is unsubstituted orsubstituted by a chlorine atom or a nitro or trifluoromethyl group, or apyridyl group, and B is a bond or a C₁₋₅ -alkylene chain, or atautomeric form thereof or a physiologically tolerated salt thereof. 2.A pharmaceutical composition for oral, parenteral or intraperitonealuse, containing per single dose from 0.1 to 100 mg/kg of body weight ofat least one imidazoloquinoxalinone I as defined in claim 1, in additionto conventional pharmaceutical ancillary substances.
 3. A pharmaceuticalcomposition for intravenous use, containing from 0.001 to 10% by weightof at least one imidazoloquinoxalinone I as defined in claim 1, inaddition to conventional pharmaceutical ancillary substances.
 4. Amethod for controlling spasms, epilepsy, anxiety or depression due toneurodegenerative disorders and neurotoxic disturbances of the centralnervous system which comprises administering to a patient in needthereof an effective amount of an imidazoloquinoxalinone I as defined inclaim
 1. 5. An imidazoloquinoxalinone of the formula I ##STR31## whereR¹ is hydrogen, branched or straight-line C₁₋₅ -alkyl or a phenyl,pyridyl or thienyl group which is unsubstituted or substituted by one ortwo chlorine atoms, one trifluoromethyl, one nitro or methylenedioxygroup,R² is hydrogen, C₁₋₅ -alkyl or C₃₋₈ -dialkylaminoalkyl, R³ is achlorine or bromine atom, a trifluoromethyl, cyano or nitro group, A ispyrrolyl, R⁴ and R⁵, which can be identical or different, are hydrogen,C₁₋₅ -alkyl, C₁₋₅ -hydroxyethyl, phenyl, phenyl substituted by achlorine atom, a trifluoromethyl or nitro group, or --COOH, --COO--C₁₋₅-alkyl, --CH₂ --NR⁶ R⁷, --CH₂ --NH--CO--R⁸ or --CH₂ --NHCONHR⁸, whereR⁶is hydrogen or C₁₋₅ -alkyl, R⁷ is hydrogen or C₁₋₅ -alkyl, and R⁸ isC₁₋₅ -alkyl, a phenyl group which is unsubstituted or substituted by achlorine atom or a nitro or trifluoromethyl group, or a pyridyl group,and B is a bond or a C₁₋₅ -alkylene chain, or a tautomeric form thereofor a physiologically tolerated salt thereof.
 6. A pharmaceuticalcomposition for oral, parenteral or intraperitoneal use, containing persingle dose from 0.1 to 100 mg/kg of body weight of at least oneimidazoloquinoxalinone I as defined in claim 5, in addition toconventional pharmaceutical ancillary substances.
 7. A pharmaceuticalcomposition for intravenous use, containing from 0.001 to 10% by weightof at least one imidazoloquinoxalinone I as defined in claim 5, inaddition to conventional pharmaceutical ancillary substances.
 8. Amethod for controlling spasms, epilepsy, anxiety or depression due toneurodegenerative disorders and neurotoxic disturbances of the centralnervous system which comprises administering to a patient in needthereof an effective amount of an imidazoloquinoxalinone I as defined inclaim
 5. 9. An imidazoloquinoxalinone of the formula I ##STR32## whereR¹ is hydrogen, branched or straight-line C₁₋₅ -alkyl or a phenyl,pyridyl or thienyl group which is unsubstituted or substituted by one ortwo chlorine atoms, one trifluoromethyl, one nitro or methylenedioxygroup,R² is hydrogen, C₁₋₅ -alkyl or C₃₋₈ -dialkylaminoalkyl, R³ is achlorine or bromine atom, a trifluoromethyl, cyano or nitro group, A is1,2,4-triazolyl, R⁴ and R⁵, which can be identical or different, arehydrogen, C₁₋₅ -alkyl, C₁₋₅ -hydroxyethyl, phenyl, phenyl substituted bya chlorine atom, a trifluoromethyl or nitro group, or --COOH,--COO--C₁₋₅ -alkyl, --CH₂ --NR⁶ R⁷, ---CH₂ --NH--CO--R⁸ or --CH₂--NHCONHR⁸,where R⁶ is hydrogen or C₁₋₅ -alkyl, R⁷ is hydrogen or C₁₋₅-alkyl, and R⁸ is C₁₋₅ -alkyl, a phenyl group which is unsubstituted orsubstituted by a chlorine atom or a nitro or trifluoromethyl group, or apyridyl group, and B is a bond or a C₁₋₅ -alkylene chain, or atautomeric form thereof or a physiologically tolerated salt thereof. 10.A pharmaceutical composition for oral, parenteral or intraperitonealuse, containing per single dose from 0.1 to 100 mg/kg of body weight ofat least one imidazoloquinoxalinone I as defined in claim 9, in additionto conventional pharmaceutical ancillary substances.
 11. Apharmaceutical composition for intravenous use, containing from 0.001 to10% by weight of at least one imidazoloquinoxalinone I as defined inclaim 9, in addition to conventional pharmaceutical ancillarysubstances.
 12. A method for controlling spasms, epilepsy, anxiety ordepression due to neurodegenerative disorders and neurotoxicdisturbances of the central nervous system which comprises administeringto a patient in need thereof an effective amount of animidazoloquinoxalinone I as defined in claim 9.